1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(2-thiazolyl)-3-quinoline carboxylic acid 2-methyl(phenylmethyl)amino ethyl ester and pharmaceutically acceptable salts

ABSTRACT

1,4,5,6,7,8-Hexahydro-4-heterocyclyl-5-oxo-quinoline derivatives and corresponding acridine derivatives and pharmaceutically acceptable salts thereof are useful antihypertensive agents.

BACKGROUND OF THE INVENTION

Pharmacological agents possessing the ability to block cellulartransmembrane influx of calcium are capable of suppressing that portionof myocardial or smooth muscle contractility which is dependent uponextracellular calcium. These pharmacological agents, termed calciumantagonists, have been proven to be useful in the treatment ofhypertension, cardiac arrhythmias, angina pectoris, cardiac myopathy andcoronary artery vasospasm (a possible cause of sudden cardiac deathsyndrome). Can. J. Physiol. Pharmacol., 57, 433 (1979); Drugs, 15, 169(1978); Acta Pharmacol. Toxicol., 43, suppl. 1,45 (1978).

In theory, calcium antagonists are thought to act by blocking calciuminflux through discrete calcium channels (slow channels) in cellmembranes. Various tissues exhibit relative differences in sensitivitytoward the calcium blocking effect achieved by certain calciumantagonists, theoretically as a result of tissue specific differences inthe calcium channels. Acta Pharmacol. Toxicol., 43, 5 (1978); loc cit.291 (1978); Microvascular Res., 5, 73 (1973); Am. Rev. Pharmacol.Toxicol., 17, 149 (1977). Calcium channels of tissues which are mostsensitive to calcium antagonist blockade are those which allow calciuminflux only when the cell membranes are electrically depolarized.Alpha-adrenergic receptor-activated calcium channels are relativelyunaffected by these agents. Circ. Res., 46, 246 (1980). This observationprovides basis for evaluation of calcium antagonism.

The vascular smooth muscle tissue from the rabbit aorta can be made tocontract when exposed to a depolarizing solution containing an elevatedpotassium ion concentration and normal amounts of calcium ions. Calciumantagonists added to the solution produce a dose dependent relaxation ofthe contracted rabbit aortic tissue. Normal contraction of the aortictissue can then be induced in the presence of a calcium antagonist bysubsequent addition of an alpha-adrenergic agonist, such asnorepinephrine, to the solution. Eur. J. Pharmacol., 53, 281 (1979);Circ. Res., 46, 426 (1980); J. Exp. Pharmacol. Therap., 174, 500 (1970).The normal contraction produced by an alpha-adrenergic agonist aftermaximal smooth muscle relaxation has been induced by a calciumantagonist, serves to distinguish the calcium blocking effect of anagent from a nonspecific depressant effect on the muscle.

DESCRIPTION OF THE INVENTION

In accordance with this invention there is provided a group of1,4,5,6,7,8-hexahydro-4-heterocyclyl-5-oxo-quinoline derivatives andcorresponding acridine derivatives and pharmaceutically acceptable saltsthereof which compounds are calcium antagonists useful in the treatmentof hypertension, cardiac arrhythmias, angina pectoris, cardiac myopathyand coronary artery vasospasm.

More specifically, the antihypertensive agents of this invention arecompounds of the formula: ##STR1## in which R₁ is alkoxy of 1 to 6carbon atoms, alkoxyalkoxy of 2 to 12 carbon atoms, or OCH₂ (CH₂)_(n)-NR₃ R₄ wherein R₃ is hydrogen or alkyl of 1 to 6 carbon atoms, R₄ isalkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms and R₃and R₄ taken together with the nitrogen atom to which they are attachedform an imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl,4-alkylpiperazinyl in which the alkyl group contains from 1 to 6 carbonatoms or morpholinyl, and n is one of the integers 0, 1 or 2;

R₂ is alkyl of 1 to 6 carbon atoms or trifluoromethyl;

R₁ and R₂ taken together represent trimethylene; and

X is substituted or unsubstituted imidazolyl or thiazolyl, wherein saidsubstituent is alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbonatoms;

or a pharmaceutically acceptable salt thereof.

The preferred compound subgenus from the standpoint of economics andease of obtaining the reactants embraces compounds of the formula:##STR2## in which

R₁ is alkoxy of 1 to 3 carbon atoms, or --OCH₂ (CH₂)_(n) --NR₃ R₄ whereR₃ is hydrogen or alkyl of 1 to 3 carbon atoms, R₄ is alkyl of 1 to 3carbon atoms or benzyl and R₃ and R₄ taken together with the nitrogenatom to which they are attached form 2-imidazolidinyl, 2-pyrrolidinyl,2-piperidyl, 1-piperazinyl, 4-alkylpiperazin-1-yl in which the alkylgroup contains 1 to 3 carbon atoms or 3-morpholinyl and n is one of theintegers 1 or 2;

R₂ is alkyl of 1 to 3 carbon atoms or trifluoromethyl, and R₁ and R₂taken together represent trimethylene;

X is substituted or unsubstituted imidazol-2-yl or thiazol-2-yl, whereinsaid substituent is alkyl of 1 to 3 carbon atoms or aryl of 6 to 8carbon atoms;

or a pharmaceutically acceptable salt thereof.

The quinoline derivatives of this invention are prepared by reaction ofequimolar amounts of 1,3-cyclohexanedione, a heterocyclic aldehyde and a3-alkyl-3-amino-acrylic acid ester as follows: ##STR3## Similarly, theacridine derivatives of this invention are prepared by reaction of twoequivalents of 1,3-cyclohexanedione, one equivalent of the heterocyclicaldehyde and ammonium acetate, thusly: ##STR4## The heterocyclicaldehydes employed in the production of the compounds of this inventionare either known compounds or may be prepared by standard procedures(Tetrahedron, 1980, 36, 2505 or Org. Prep and Proced., 1983, 15 19). Theaminoalkyl esters may be prepared by formation of the substitutedaminocrotonate in situ via ammonolysis of the desired aminoalkylacetoacetic acid ester.

The pharmaceutically acceptable salts of the antihypertensive agents ofthis invention are prepared directly by neutralization of the free baseor by metathetical displacement. The physiological acceptable salts maybe formed with organic or inorganic acids such as hydrochloric,hydrobromic, phosphoric, sulfuric, sulfonic, nitric, methylsulfonic,acetic, maleic, succinic, fumaric, tartaric, citric, salicyclic, lactic,naphthalenesulfonic acid, and the like.

The compounds of this invention were initially shown to exhibit Ca⁺²antagonism in rabbit aortic strips wherein the strips were contracted inan organ bath containing a modified physiological salt solution(Broekaert et al., Europ. J. Pharmacol. 53 281 (1979)) in which 100millimoles potassium ion had been substituted on an equimolar basis forsodium ion. After a stable active tension has developed in the strip, asmeasured by Statham UC-2 force transducers and recorded on an eightchannel Beckman Dynograph Polygraphic Recorder, an amount of theantagonist was added to the organ bath to make a 10⁻⁵ molarconcentration of antagonist. The depressent effect, expressed as percentrelaxation, was taken from the mean of at least two experiments. Aftermaximum Ca⁺² antagonist induced relaxation was obtained, a maximal doseof norepinephrine (10⁻⁵ moles) was added to the organ bath to determinewhether normal alpha-adrenergic responses were still effected and showthat the compound being tested was not a general depressant.

The in vivo blood pressure lowering ability of the compounds of thisinvention was established by measuring the systolic pressure ofspontaneously hypertensive rats with a Decker Caudal Plethysmograph orsimilar sensor device. The compound being tested is administered togroups of four rats and their blood pressure is read prior to compoundadministration and at 1.5 and 4 hours after compound administration.Depending upon the behavior of the compound being tested, the scheduleof blood pressure readings and route of administration is modifed.Initially the compounds are administrered orally but where compoundsolubility is a factor, the compounds may be administered parenterally(i.e., i.p., i.m., s.c., i.v., etc.) as desired. The compounds of thisinvention were initially administered orally at a standard testing doseof 50 mg/kg.

Based upon the activity profile elicited by the compounds of thisinvention in the above-described standard scientifically recognized testmodels, the compounds are established as hypotensive agents useful inthe treatment of hypertension and conditions characterized byconstrictive blood flow in coronary arteries. For that purpose, thecompounds may be administered orally or parenterally in suitable dosageforms compatable with the route of administration, whether oral,intraperitoneal, intramuscular, intravenous, intranasal, buccal, etc.The effective dose range determined in the animal test models has beenestablished at from 10 to about 50 milligrams per kilogram host bodyweight to be administered in single or plural doses as needed to obtainthe desired hypotensive response. The specific dosage regimen for agiven patient will depend upon age, pathological state, severity ofdysfunction, size of the patient, etc. Oral administration is performedwith either a liquid or solid dosage unit in any conventional form suchas tablets, capsules solutions, etc., which comprise a unit dose (e.g.from about 25 milligrams to about 4 grams) of the active ingredientalone or in combination with adjuvants needed for conventional coating,tableting, solubilizing, flavor or coloring. Parenteral administrationwith liquid unit dosage forms may be via sterile solutions orsuspensions in aqueous or oleagenous medium. Isotonic aqueous vehiclefor injection is preferred with or without stabilizers, preservativesand emulsifiers.

The following examples illustrate the preparation of a representativenumber of compounds of this invention. After each example, theantihypertensive activity is reported as a decrease in blood pressure(B.P.) in terms of millimeters of mercury (mmHg) at the time indicatedafter 50 mg/kg oral dosing. Similarly, the Ca⁺² antagonist activity ofthe compound is presented in terms of present relaxation (P.R.) at 10⁻⁵M concentrations.

EXAMPLE 11,4,5,6,7,8-Hexahydro-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-quinolinecarboxylicacid ethyl ester

A mixture of N-methyl-imidazole-2-carboxaldehyde (4.9 g, 0.045 mole),1,3-cyclohexandione (5.8 g, 0.045 mole), and ethyl-3-aminocrotonate(5.04 g, 0.045 mole), in 50 mL of absolute ethanol was refluxed for 24hours. The reaction mixture was cooled and the separated solid wasfiltered and recrystallized from a hexane-ethylacetate (1:1) mixture toafford 5.2 g (37% yield) of the title compound, m.p. 271°-272° C.; MS,m/e 315 (M⁺); NMR (CDCl₃) δ 1.0 (t, 3 H, CCH ₃), 1.5-2.4 (m, 6 H,cyclohexanone), 2.5 (s, 3 H, ═CCH₃), 3.9-4.1 (q, 2 H, CH₂ C), 4.0 (s, 3H, NCH₃), 5.2 (s, 1 H, dihydropyridine-H), 6.3 (d, 1 H, imidazole-H),6.5 (d, 1 H, imidazole-H) and 9.5 (s, 1 H, NH).

Analysis for: C₁₇ H₂₁ N₃ O₃

Calculated: C, 64.76; H, 6.66; N, 13.33.

Found: C, 64.28; H, 6.72; N, 13.00.

B.P.=-22 at 1.5 hours and -18 at 4 hours.

P.R.=14.

EXAMPLE 21,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(2-thiazolyl)-3-quinolinecarboxylic acid 2-Methyl(phenylmethyl)amino ethyl ester

To a mixture of 1,3-cyclohexandione (5.6 g, 0.05 mole),2-(N-benzyl-N-methylamino)ethyl acetoacetate (12.4 g, 0.05 mole) andammonium acetate (7.7 g, 0.1 mole) in 50 mL of absolute ethanol wasadded (5.5 g, 0.05 mole) of thiazole-2-carboxaldehyde and the reactionmixture was heated at reflux for 12 hours. The solution was cooled,evaporated under reduced pressure, and the residue was extracted in 200ml of methylene chloride. The methylene chloride layer was washed withwater, dried and evaporated in vacuo. The brown oil was separated byhigh performance liquid chromatography (using 30% methanol-ethyl acetatemixture as the eluent) to afford 9.0 g (43% yield) of the titlecompound, m.p. 119°-120° C.; MS, m/e 437 (M⁺); NMR (CDCl₃) δ 1.6-2.5 (m,6 H, cyclohexanone), 2.2 (s, 3H, CCH₃), 2.3 (s, 3 H, NCH₃), 3.5 (s, 2 H,CH₂ φ), 3.6 (t, 2 H, CCH₂ N), 4.1 (t, 2 H, OCH₂ C), 5.5 (s, 1 H,dihydropyridine-H), 7.1 (d, 1H, thiazole-H), 7.2 (s, 5H, φ), 7.6 (d, 1H, thiazole-H) and 8.6 (s, 1 H, NH).

Analysis for: C₂₄ H₂₇ N₃ SO₃

Calculated: C, 65.90; H, 6.17; N, 9.61.

Found: C, 65.83; H, 6.22; H, 9.51.

The dihydrochloride salt was prepared by dissolving the title compoundin ethanol saturated with hydrogen chloride gas. The alcohol wasevaporated, and the residue was recrystallized from ethanol, m.p.154°-158° C.

B.P.=-47 at 1.5 hours.

P.R.=21.1.

EXAMPLE 31,4,5,6,7,8-Hexahydro-2-trifluoromethyl-4-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-quinolinecarboxylicacid ethyl ester

To a stirred mixture of 2.3 g (0.02 mole) of 1,3-cyclohexandione,ethyl-4,4,4-trifluoroacetoacetate (3.3 g, 0.02 mole) and ammoniumacetate (4.9 g, 0.4 mole) in 50 mL of absolute ethanol, (2.0 g, 0.02mole) of N-methylimidazole-2-carboxaldehyde was added. The reactionmixture was refluxed for 24 hours and allowed to cool to roomtemperature. The solvent was evaporated in vacuo, and the residue wasseparated by high performance liquid chromatography (30%methanol-ethylacetate mixture as the eluent) to afford 0.5 g (7% yield )of the title compound, m.p. 197°-198° C.; MS, m/e 369 (M⁺); NMR (CDCl₃)δ1.0 (t, 3 H, CCH₃), 1.5-2.4 (m, 6 H, cyclohexenone), 3.7 (s, 3 H,NCH₃), 4-4.1 (q, 2 H, CH₂ C), 5.0 (s, 1 H, dihydropyridine-H), 6.5 (d, 1H, imidazole-H), 6.8 (d, 1 H, imidazole-H) and 9.6 (s, 1 H, NH).

Analysis for: C₁₇ H₁₈ F₃ N₃ O₃.1/2H₂ O

Calculated: C, 53.96; H, 5.02; N, 11.11.

Found: C, 54.30; H, 5.01; N, 10.80.

B.P.=-10 at 4 hours (at a dose of 35 mg/kg).

R.P.=10.8.

EXAMPLE 41,4,5,6,7,8-Hexahydro-4-(thiazol-2-yl)-5-oxo-3-quinolinecarboxylic acidethyl ester

The procedure of Example 1 was utilized with the exception thatthiazole-2-carboxaldehyde was used instead ofN-methyl-imidazole-2-carboxaldehyde to afford 72% yield of the titlecompound, m.p. 239°-240° C., MS, m/e 318 (M⁺); NMR (CDCl₃) δ 1.1 (t, 3H, CCH₃), 1.9-2.5 (m, 6 H cyclohexanone), 4.0 (q, 2 H, CH₂ C), 5.4 (s, 1H, dihydropyridine-H), 7.5 (d, 1 H, thiazole-H), 7.7 (d, 1 H,thiazole-H), and 8.0 (s, 1 H, NH).

Analysis for: C₁₆ H₁₈ N₂ SO₃

Calculated: C, 60.37; H, 5.66; N, 8.80.

Found: C, 60.28; H, 5.84; N, 8.68.

B.P=-21 at 4 hours.

P.R.=9.

EXAMPLE 51,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(1-methyl-1H-imidazol-2-yl)-3-quinolinecarboxylicacid 2-methyl(phenylmethyl)amino ethyl ester

The procedure in Example 2 was utilized with the exception thatN-methylimidazole-2-carboxaldehyde was used instead ofthiazole-2-carboxaldehyde to afford 4.9 g (22% yield) of the titlecompound, m.p. 184°-187° C.; MS, m/e 434 (M⁺).

Analysis for: C₂₅ H₃₀ N₄ O₃.H₂ O

Calculated: C, 66.37; H, 7.0; N, 12.3.

Found: C, 66.83; H, 6.81; N, 12.74.

B.P.=-13 at 4 hours.

P.R.=11.3

EXAMPLE 6 3,4,6,7,9,10-Hexahydro-9-(2-thiazolyl)-1,8(2H,5H)-acridine

A mixture of 5.08 (0.045 mole) of thiazole-2-carboxaldehyde, 11.6 g(0.09 mole) of 1,3-cyclohexanidione and (5.0 g, 0.06 mole) of ammoniumacetate in 50 mL of absolute ethanol were refluxed for 24 hours. Thereaction mixture was cooled and filtered. The solid was recrystallizedfrom ethanol to afford 3.7 g (30% yield) of the title compound, m.p.278°-281° C.; MS, m/e 300 (M⁺); NMR (CDCl₃) δ1.7-2.1 (m, 6 H,cyclohexenone), 2.5-2.6 (m, 6 H, cyclohexenone), 5.4 (s, 1 H,dihydropyridine-H), 7.8 (d, 1 H, thiazole-H), 7.9 (d, 1 H, thiazole-H)and 9.7 (s, 1 H, NH).

Analysis for: C₁₆ H₁₆ N₂ SO₂

Calculated: C, 64.00; H, 5.3; N, 9.33; S, 10.66.

Found: C, 63.68; H, 5.33; N, 9.13; S, 10.42.

The hydrochloride salt was prepared following the procedure described inExample 2, m.p. 234°-235° C.

Analysis for: C₁₆ H₁₆ N₂ SO₂.HCl

Calculated: C, 57.05; H, 5.05; N, 8.32.

Found: C, 56.79; H, 5.0; N, 8.16.

B.P.=-19 at 4 hours.

EXAMPLE 73,4,6,7,9,10-Hexahydro-9-(1-methyl-1H-imidazol-2-yl)-1,8(2H,5H)-acridine

The procedure in Example 6 was utilized with the exception thatN-methylimidazole-2-carboxaldehyde was used instead ofthiazole-2-carboxaldehyde to afford 9.2 g (69% yield) of the titlecompound, m.p. 285°-287° C.

Analysis for: C₁₇ H₁₉ N₃ O₂

Calculated: C, 68.68; H, 6.39; N, 14.14.

Found: C, 68.82; H, 6.52; N; 13.93.

B.P.=-4 at 1.5 hours.

What is claimed is:
 1. The compound which is1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-4-(2-thiazolyl)-3-quinolinecarboxylic acid 2-methyl(phenylmethyl)amino ethyl ester or apharmaceutically acceptable salt thereof.